Abstract 2703: Evaluation of the effect of tumor-targeted and immunomodulating nanoparticles on the activity of cytotoxic T cells using CAR T cells as an <i>in vitro</i> model
Authors: Kory Wells, Tongrui Lui, Lei Zhu, Chrystal Paulos, Lily Yang
Journal: Cancer Research (2023)

Abstract In solid tumors, there are multiple barriers that prevent anticancer agents and T cells from being able to be delivered into and reach tumor cells. For effective antitumor activity, it is necessary to have direct interactions between cytotoxic T cells and tumor cells. Hyaluronic acid and Iron oxide both have distinctive properties that are advantageous for the development of biocompatible and biodegradable nanoparticle drug delivery systems for cancer. We have developed several targeting and immunomodulatory ligands that can be conjugated to the nanoparticles while carrying chemotherapy or molecular targeted agents for targeted cancer therapy as shown in Table 1. Although the therapeutic efficacy of those targeted nanoparticles has been demonstrated in mouse tumor models, the effect of nanoparticles and their payload drugs on the activities of tumor specific cytotoxic T cells is still unclear. To determine the effect of those nanoparticles on T cell immune responses, CAR T cells provided a well-suited in vitro cellular model. In this study, anti-mesothelin CAR T cells generated from lentiviral CAR T vector transduced T cells were incubated with nanoparticle/drugs and free drugs. The effect of various nanoparticles on CAR T cell viability, and in vitro cytotoxicity on pancreatic cancer cells was evaluated by live/dead, Alamarblue and SRB proliferation Assays. Our results showed that the incubation of CAR T cells with targeted nanoparticles/drugs did not reduce CAR T cells' viability and did not inhibit T cells' activity in killing tumor cells. The ATFmmp14-HANP/SN38 nanoparticle showed an enhanced effect of CAR T cells. Thus, this nanoparticle/drug has the potential for the development of combination therapy with CAR T cells to improve the CAR T cell delivery while synergizing anti-tumor effect by targeted drug delivery, stroma modulation, and tumor cell killing by drug and CAR T cells. Table 1. Nanoparticle formulations overview Nanoparticle Types Target Payload Mechanism of action Observed Results (in vivo) Observed Results (in vitro) ATFmmp14-HANP/SN38:ATFmmp14 conjugated HANP uPAR CD44 SN38 (an active metabolite of irinotecan) Inhibits DNA topoiso-merase I, causing DNA single strand breaks and DNA damage. Significant tumor growth inhibition in human pancreatic and breast cancer PDX models. HANP more effective towards pancreatic cell line and less toxic against CAR T cells: Greater anti-tumor with combination HANP/GKT831: HANP CD44 Setanaxib (GKT831:an inhibitor of NOX1 and NOX4 Reduce the level of reactive oxygen species (ROS): DNA repair downregulation, increases DNA damage Efficient delivery into mouse breast PDX tumors and sensitizing tumor cells to radiotherapy and DNA damaging agents. Nontoxic towards CAR T cells: limited additional therapeutic effects PDY1-HANP/Avasimibe: PD-L1 blocking PDY1 peptide conjugated HANP PD-L1 CD44 Avasimibe (Ava), an inhibitor of acyl-Coenzyme A:cholesterolacyltransferase Decreases intracellular cholesterol.Inhibit tumor cell growth, Activate cytotoxic T cells Efficient delivery into mouse colon tumors, Inhibition of tumor growth: Increased levels of CD8+ T cells and CD68+ Macrophages in tumors Nontoxic towards pancreatic cell lines and CAR T cells: limited additional therapeutic effects ATFmmp14-IONP-DOX: ATFmmp14 conjugated IONP uPAR Doxorubicin Direct DNA damage and inhibits DNA repair by inhibiting topoisomerase Significantly inhibited tumor growth in human pancreatic and breast cancer PDX model ATFmmp14-IONP/DOX more effective towards pancreatic cancer cell lines and less toxic against CAR T cells: slightly increased killing of tumor cells with combination ATFmmp14: Amino terminal fragment (ATF) of uPA fused with MMP14 catalytic domain; PD1Y: PD1 peptide mimetic that binds to and inhibit PD-L1 HANP: Hyaluronic acid nanoparticle; IONP: Iron oxide nanoparticle Citation Format: Kory Wells, Tongrui Lui, Lei Zhu, Chrystal Paulos, Lily Yang. Evaluation of the effect of tumor-targeted and immunomodulating nanoparticles on the activity of cytotoxic T cells using CAR T cells as an in vitro model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2703.